Petra De Sutter Div. Reproductive Medicine UZ Gent Clinical indications for androgen assays in...
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Transcript of Petra De Sutter Div. Reproductive Medicine UZ Gent Clinical indications for androgen assays in...
Petra De SutterDiv. Reproductive Medicine
UZ Gent
Clinical indications for
androgen assays in gynaecology
Androgens and women
• Source of androgens:– Ovarian theca and stromal cells <LH control
– Adrenal cortex
– Peripheral (< precursors)
• Function?– Estradiol production (aromatisation in granulosa cells <FSH
control)
– Sex drive, muscular mass, etc…
• Which?– DHEA(S) > A’dione > Testo-DHT
• Postmenopauzal:– A’dion mainly adrenal source
17-α-hydroxylase
desmolase
Androgeen productie bij de vrouw in de vruchtbare jaren
Androgeen precursors
DHEAS: Dihydroepiandrosteron sulfaat
DHEA: Dihydroepiandrosteron
A: Androstenedion
TestosteronTestosteron
60%60%
20%20%
90%90%
50%50%
40%40%
25-35%25-35%
50-75%50-75%
ovaria bijnieren
o.i.v. LH o.i.v. ACTH
Totaal T bij de vrouwTotaal T bij de vrouw 1 - 4 1 - 4 nmol nmol/L/L 0,5 - 3 0,5 - 3 nmolnmol/L/L
66% SHBG
Bio-availabletestosteron
30% albumine
Normale verdeling van TNormale verdeling van Tin het bloed van de vrouwin het bloed van de vrouw
CBG CBG CortisolCortisol Binding Globuline Binding GlobulineSHBG SHBG Sex HormoneSex Hormone Binding Globuline Binding Globuline
T is stevig gebonden,dus niet beschikbaar
1,3%vrij T
2,3%CBG
Oorzaken van androgeentekort bij de vrouw
1.Verminderde androgeenproductie
In ovaria: - normale veroudering- bilaterale ovariëctomie- radiotherapie - chemotherapie - GnRH-agonisttherapie
In bijniercortex: - normale veroudering- primaire/secundaire bijnierschorsinsufficiëntie- bilaterale adrenalectomie
In ovaria en bijniercortex: panhypofysaire insufficiëntie
Illustration of the 50% parallel decrease in serum DHEA, DHEA-S, and testosterone between the ages of 21 and 40 years in
healthy women
Oorzaken van androgeentekort bij de vrouw (vervolg)
2. Verhoogde binding van circulerende androgenen aan SHBG → verlaagde vrije androgeenfractie:
- oestrogeentherapie
- (hyperthyreoïdie)
3. Gestoorde androgeenreceptorwerking:
- aangeboren volledige of partiële androgeeninsensitiviteit
- inname van androgeenreceptorblokkeerders: cyproteronacetaat, spironolacton, flutamide
De vrouwelijke seksuele respons: het biopsychosociaal model (R.Basson)
Emotionele intimiteit
Emotionele en fysieke tevredenheid
Zin in seks & verdere arousal
Seksuele stimuli
Arousal
+ +motivatie voor
++
Spontane seksuele honger (drive)
Oxytocine ??
Oestrogenen
Androgenen
Female androgen insufficiency: Princeton consensus (Fertil Steril 2002;77:660-5)
• Symptomen: - verminderd welbevinden en neerslachtige stemming
- blijvende onverklaarde vermoeidheid
- verstoorde seksuele respons (libido)
• Omdat oestrogenen ook een invloed hebben op stemming en seksuele respons, kan de diagnose alleen gesteld worden bij vrouwen met adequate oestrogenisatie
• Vrije testosteronwaarde ≤ 25ste percentiel van normale waarden bij vrouwen tussen 20 en 40 jaar
Classification of Female Sexual Dysfunction*
Sexual desire disorders Hypoactive sexual desire disorder Sexual aversion disorder
Sexual arousal disorder
Orgasmic disorder
Sexual pain disorders Dyspareunia Vaginismus
Other sexual pain disorders
*Each disorder is subtyped as lifelong versus acquired, generalized versus situational, and as to etiologic origin (organic, psychogenic, mixed, unknown).
Androgen excess
• Hyperandrogenism
(virilisation)– Acne
– Hirsutism
– alopecia
• Cycle disturbances– PCOS
• HAIR-AN syndrome– Hyperandrogenism
– Insulin resistence
– Acanthosis nigricans
Hyperandrogenism• = any clinical or laboratory evidence of androgen excess in women. • Most common clinical presentation of hyperandrogenism in
reproductive-aged women is hirsutism or acne with or without evidence of anovulation such as oligo- or amenorrhea or dysfunctional uterine bleeding.
• Elevated blood levels of androgens without clinical symptoms is referred to as cryptic hyperandrogenism.
• Hirsutism = presence of course terminal hairs in androgen-dependent areas on the face and body in women >< hypertrichosis =excessive growth of thin vellus hair at any body site (usually familial or associated with anorexia nervosa or thyroid dysfunction, or with medications such as phenytoin, minoxidil or cyclosporin.
• Hirsutism affects 2-10% of women between 18 and 45• Source of psychological discomfort • Scored by Ferriman-Gallwey score
Causes of Hyperandrogenism
Common
Polycystic Ovary Syndrome 80%
Idiopathic Hirsutism 15%
Uncommon
Late-Onset 21-Hydroxylase Deficiency 1-5%
Rare < 1%
Steroidogenic Enzyme Deficiencies 3-hydroxysteroid dehydrogenase 17-ketosteroid reductase aromatase
Androgen Secreting Tumors of Ovary or Adrenal
Ovarian Hyperthecosis (a PCOS variant)
Other EndocrineHyperprolactinemiaCushing syndromeDefects in cortisol metabolismAcromegaly
Evaluation of Hyperandrogenism
History
OnsetProgression
Onset at menarche suggests PCOS, idiopathic hirsutism or 21-hydroxylase deficiency. Onset distinct from menarche suggests tumor.Rapid progression of hirsutism or other symptoms suggests tumor
Physical Examination
Hirsutism and acne Virilization
PCOS or idiopathic hirsutismOvarian or adrenal tumor, hyperthecosis
Laboratory Tests
Total and free testosterone17-hydroxyprogesteroneProlactin, TSH
Confirm hyperandrogenism, rule out tumorRule out mild 21-hydroxylase deficiency. Perform ACTH stimulation test in patients of Askenazi Jewish descent In all patients with oligo-amenorrhea or dysfunctional bleeding
Imaging
Transvaginal ultrasoundCT of adrenal glands
Confirm polycystic ovaries, rule out ovarian tumorIf ovarian ultrasound is normal and tumor is suspected
PCOS
• heterogenous disease• 5-10 % of all adult women• 20 % of all infertile women• 80-90% of all anovulatory women• criteria for diagnosis (2 out of 3):
PCO image on ultrasound increased androgens (clinically / chemically) irregular cycles
• Validity of Rotterdam consensus?
PCOS
• often (but not always!): obesity insulin resistence (cave diabetes!) increased LH and LH/FSH
• PCO (20%) ≠ PCOS (5-10%)• increased androgens
< adrenal, ovary acne, hirsutism
• irregular cycles -> infertility
cameleon
• symptoms: irregualr cycles: 30-50% amenorrhea: 20-50% hirsutism: 60-70% obesity: 30-40% acne: 30% infertility: 20-70%
• lab: hyperandrogenism: 30-50% increased LH: 40-50%
Normal ovary PCO ovary
Prevalence
• genetic factors: families, twins insulin? Hormone receptors? exogeneous factors
• racial factors Genetic? Food? Surroundings? Asian > mediterranean > Caucasian women
Short term problems
• obesity, acne and hirsutism -> cosmetic problem, psychologic problems, low self image, depression
• irregular cycles -> infertility
• during pregnancy increased risk for miscarriage increased risk for pregnancy diabetes and hypertension
Long term health risks
• obesity -> cariovascular disease, hypertension, myocardial infarction
• insulin resistence -> diabetes• metabolic syndrome or syndrome X
-> obesity, hypercholesterolaemia, atherosclerosis, diabetes
• irregular cycles -> endometrium hyperplasia and cancer
Importance of obesity
• obesity -> does NOT lead to PCOS
• women with PCOS who also are obese have an increased chance to develop symptoms: obesity worsens PCOS !
• weight loss therefore ameliorates PCOS symptomatology
Treatment
• weight loss (>5% often normalizes cycle regularity)• OCS (cycle reg, decreasing androgens)
typically Diane 35 (CA) or Yasmin (drosperinone)
• if child wish: hormonal stimulation• if hirsutism: OCS + CA or cosmetic• metformin ??? Only if IR• dexamethasone >< adrenal androgens• (statins >< lipid disturbances, ovarian androgens)
Life style modification !
TABLE 1. Clinical Impact of Lifestyle Management in PCOS From: HOEGER: Clin Obstet Gynecol, Volume 50(1).March 2007.277-294
Thank you for your attention